This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project is centered on the genetic and molecular control of E3 ubiquitin ligases in stem cell differentiation and neoplasia. The underlying hypothesis, based on the project leader's work recently published in PNAS (2010) and about to be published in Nature Immunology, provides an innovative approach to stem cell differentiation. The hypothesis states that the presence of c-Cbl ring finger mutant protein in HSCs results in altered signal transduction pathways and thereby causes transformation of normal HSCs into leukemic stem cells. In order to prove or disprove this hypothesis, the project leader has developed the following specific aims: 1) Investigate the myeloid differentiation defects in the c-Cbl -/- mice. 2): Identify the hematopoietic compartment that causes AML in c-Cbl A/- mice. 3) Decipher the dominant negative functions of c-Cbl Ring Finger mutant protein in the development of acute myelogenous leukemia (AML). 4) Dissect the requirement of c-Kit/PI3K/AKT/Erk signal transduction pathways in the development of myeloid leukemia in Cbl A/- mice. Overall, this work promises to provide novel ways to understand stem cell differentiation and may also provide directions for therapeutics that may aid the treatment of patients with c-Cbl mutations.